5,5-diphenylpent-4-enoic acids and related compounds

ABSTRACT

SUBSTITUTED ALKENOIC ACIDS HAVING TWO PHENYL OR LOWER ALKOXYPHENYL GROUPS AND CERTAIN DERIVATIVES HAVE BEEN FOUND TO HAVE EXTROGENIC, E.G., ANTI-FERTILITY PROPERTIES FOR TREATING MENOPAUSAL DISORDERS OR FOR ESTROGENIC REPLACEMENT. TYPICAL COMPOUNDS ARE 2-CARBOXY-5,5-DIPHENYL-4METHYLPENT--4-ENOIC ACIDS, 2-METHYL-4-ETHYL-5,5-DIPHENYL2-CARBOXYPENT-4-ENOIC ACID AND 2,4-DIMETHYL-5-PHENYL5-(4-METHOXY-PHENYL)PENT-4-ENOIC ACID. THE NEW COMPOUNDS ARE FORMULATED AS TABLETS AND CAPSULES FOR ORAL USE AND AS INJECTABLE WITH STERILE WATER,

United States Patent 3,829,474 5,5-DIPHENYLPENT-4-ENOIC ACIDS AND RELATED COMPOUNDS Eric Harold Billett, Harlowe, and David Miller, Sevenoaks, England, assignors to Beecham Group Limited, Brentford, Middlesex, England No Drawing. Original application Aug. 3, 1970, Ser. No. 60,729, now Patent No. 3,736,347. Divided and this application Aug. 31, 1972, Ser. No. 285,366

Int. Cl. C07c 63/46, 63/48, 63/76 US. Cl. 260-515 R 7 Claims ABSTRACT OF THE DISCLOSURE Substituted alkenoic acids having two phenyl or lower alkoxyphenyl groups and certain derivatives have been found to have estrogenic, e.g., anti-fertility properties for treating menopausal disorders or for estrogenic replacement. Typical compounds are Z-carboxy-S,5-diphenyl-4- methylpent-4-enoic acids, 2-methyl-4-ethyl-5,S-diphenyl- 2-carboxypent-4-enoic acid and 2,4-dimethyl--phenyl- 5-(4-methoxy-phenyl)pent-4-enoic acid. The new compounds are formulated as tablets and capsules for oral use and as injectables with sterile water.

wherein R is a 1-6 C alkyl group, or a hydrogen or halogen atom; X is CH or C-H -CH(CH R is a hydrogen atom or a 1-6 C alkyl or 6-10 C aryl group; R is a hydrogen atom or a carboxyl group; and each of R and R is a hydrogen atom or a 1-6 C alkoxy group; except that when R R are all hydrogen atoms, R is not a hydrogen atom, and non-toxic salts, esters and amides thereof.

The invention also provides a process for preparing the substituted alkenoic acids of formula (I) as defined above, which process comprises reacting a diphenyl compound of the formula:

wherein M is an alkali metal and R is a 1-6 C alkyl group, and if desired hydrolysing the resulting ester to 3,829,474 Patented Aug. 13, 1974 give a compound of formula (I) in which R is a carboxyl group and optionally decarboxylating by heating to give a compound of formula (I) in which R is a hydrogen atom, and optionally forming salts, esterifying or forming amides.

Aprropriate substituent groups are introduced into the products in known manner. For example, the acids of formula ('I) may be esterified, preferably with hydrocarbyl alcohols, to give hydrocarbyl esters, or they may be converted to the acid chlorides, for example with thionyl chloride, and these on treatment with ammonia give the corresponding amides.

The starting compounds of formula (H) are prepared in known manner. Particularly they may be prepared by reacting a ketone of the formula:

with an ester of the formula:

BrCHR-COOR wherein R, R R and R are as defined above, in presence of zinc to give an ester of the formula:

and treating this ester with a dehydrating agent such as phosphorus oxychloride to give an ester of the formula:

C=CR.COOR

@ R1 (VI) and reducing this ester with a complex metal hydride, then converting the hydroxy group in the resulting alcohol to group Z.

The invention also provides a pharmaceutical composition comprising a compound of formula (I), together with a pharmaceutically acceptable carrier. Suitable carriers include binders, lubricants and other adjuvants for tablet or granular compositions, or soft gelatin capsules, or sterile water for parenteral use.

The following Examples illustrate the invention.

EXAMPLE 1 1-Bromo-3,3-diphenyl-2-methylprop 2 ene (27.6 g.) was added dropwise to sodio-diethylmalonate [from diethyl malonate (16.0 g.) and sodium (2.3 g.) in ethanol (50 ml.)] to maintain a temperature of 50 C. Sodium bromide separated. After heating under reflux for 3 hours, ethanol was removed in vacuo, water was added, and the product extracted into ether. Removal of solvent after drying (Mg'SO gave a viscous oil (37.0 g., which was saponified by heating with aqueous potassium hydroxide (20 g. in 30 ml. water) under reflux for 3 hours. After acidification, work up via extraction into ether in the usual way gave a hard resinous material which crystallised from ethyl acetate-light petroleum (b.p. 60-80 C.) to give Z-carbOxy-iS-diphenyl-4-methylpent-4-enoic acid (15 g., 48%), m.p. 151 C. decomp. (Found: C, 73.6; H, 6.2. C H O requiresfC, 73.5; H, 5.85%).

1Bromo-3,3-diphenyl-2-methylprop-2-ene was prepared (95%) by the action of 48% hydrobronic acid (5 X excess) at room temperature for 5 hours on 3,3-diphenyl- 2-methylprop-2-en-1-ol. It was used without further purification.

3,3-Diphenyl-Z-methylprop-Z-en-I-l (95%) m.p. 45- 47 C. ex light petroleum (b.p. 60-80 C.) (Found: C, 85.8; H, 7.5. C H O requires: C, 85.7; H, 7.2%), was in turn prepared by refluxing ethyl a-methyl-[i-phenyL cinnamate (35.0 g.) (Gazz. Chim. Ital., 1927, 57, 545 550) with lithium aluminium hydride (11.8 g.) in ether (1 l.) for 24 hours.

EXAMPLE 2 Z-Carboxy-5,5-diphenyl-4-methylpent-4-enoic acid (2.0 g.) was heated in vacuo in an oil bath at 160 C. for 30 minutes. Evolution of carbon dioxide ceased after 15 minutes. Cooling and scratching with a glass rod furnished 5,5-diphenyl-4-methylpent-4-en0ic acid (1.7 g., 100%), m.p. 7475 C. (Found: C, 81.4; H, 7.0. C H O requires: C, 81.2; H, 6.8%.)

EXAMPLE 3 1-Bromo-3,3-diphenyl-2-methylprop 2 ene (27.6 g.) was added dropwise to sodio-methyl diethyl malonate [from diethyl methylmalonate (17.3 g.) and sodium (2.3 g.) in ethanol (50 ml.)] to maintain a temperature of 60 C. Proceeding as in Example 1 gave 2-carb0xy-2,4- dimethyl5,5-diphenylpent-4-en0ic acid (20 g., 61%), m.p. 175-176 C. ex ethyl acetate-light petroleum (b.p. 60-80C.) (Found: C, 73.7; H, 6.15. C H O requires: C, 74.1; H, 6.2%.)

EXAMPLE 4 -2-Carboxy-2,4-dimethyl-5,5-diphenylpent-4-enoic acid (2.0 g.) was heated in vacuo in an oil bath above its melting point as in Example 2 to give 2,4-dim'ethyl-5,5- diphenylpent-4-en0ic acid (1.67 g., 98%), m.p. 108-109 C. ex ethyl acetate-light petroleum (b.p. 60-80 0.). (Found: C, 81.3; H, 7.2. C H O requires: C, 81.4; H, 7.2.)

The action of refluxing methanol-hydrogen chloride on the acid gave its methyl ester (85%), m.p. 5657C. ex. ethanol-water. (Found: C, 81.4; H, 7.95. C H O requires: C, 81.6; H, 7.5%.)

EXAMPLE 5 1-Bromo-3,3-diphenyl-2-methylprop 2 ene (28.6 g.) was added dropwise to sodio-phenyl diethyl malonate [from diethyl phenylmalonate (23.6 g.) and sodium (2.3 g.) in ethanol (50 ml.)] to maintain a temperature of 60 C. Proceeding as in Example 1 resulted in decarboxylation at the saponification stage, and working up yielded 2,5,5- triphenyl-4-methylpent-4-enoic acid (13 g., 38%), m.p. 127128 C. ex ethyl acetate-light petroleum (b.p. 60- 80 (2.). (Found: C, 84.1; H, 6.4. C H O requires: C, 84.2; H, 6.5%.)

EXAMPLE 6 A solution of 1,1-diphenyl-2-bromomethylbut-l-ene (29 g.) in dry tetrahydrofuran was added slowly to a stirred solution of sodio-methyl diethyl malonate (19.6 g.) in the same solvent under reflux, and refluxing was continued for 30 minutes after the addition. Then most of the solvent was evaporated and the residue was taken up in ethanolic potassium hydroxide with addition of a small amount of water to give a clear solution. The mixture was refluxed for 34 hours, evaporated to small bulk extracts were washed with water (100 ml.), dried and evaporated to give Z-methyl-4-ethyl-5,5-diphenyl-2-carboxypent-4-enoic acid, yield 27.4 g.

This acid was dried and heated at 160-200 C. for 15 minutes, and the product was recrystallised from light petroleum to give Z-methyl-4-ethyl-5,5-dipheny[pent-4- enoic acid, 23.7 g. In. 70 C. (Found: C, 81.4; H, 7.5. C H O requires: C, 81.6; H, 7.5%.)

The starting 1,1diphenyl-2-br0mo-rnethylbut-l-ene was prepared by treating the corresponding Z-hydroxy compound with 48% hydrobromic acid. The Z-hydroxy com pound was prepared by reduction of ethyl 2-ethyl-3 phenylcinnamate, itself prepared from benzophenone and ethyl a-bromobutyrate.

EXAMPLE 7 1-Bromo-3,3-diphenyl-2-methylpr0p-2-ene, described in Example 1, was allowed to react with sodio-ethyl diethyl malonate as described in Example 6. The resulting diester was hydrolysed and decarboxylated to give 4-methyl-2- ethyl-5,5-diphenylpent-4-en0ic acid, 111. 70C. (Found: C, 81.4; H, 7.5. C H O requires: C, 81.6; H, 7.5%.)

EXAMPLE 8 (a) 2,4-Dimethyl-5,5-diphenylpent-4-enoic acid (10 g.) was refluxed with thionyl chloride (20 g.) for 15 minutes, and the excess of thionyl chloride was removed under vacuum. The resulting acid chloride (1 g.) was allowed to react with methanol (excess) in dichloromethane (25 ml.) at 25 C. for 1 hour, then evaporation gave the methyl ester, m. 567 C. after recrystallisation from light petroleum. (Found: C, 81.4; H, 7.9. C 'H O requires: C, 81.6; H, 7.5%.)

(b) By using n-heptanol instead of methanol the nheptyl ester was prepared similarly, and it had b.p. 190 C./0.5 mm. (Found: C, 82.4; H, 9.0. C H O' requires: C, 82.5; H, 9.0%.)

(c) The starting acid was neutralised with sodium hydroxide in aqueous solution to give on evaporation the sodium salt. (Found: C, 75.3; H, 6.4; Na, 7.3. C H O Na requires: C, 75.5; H, 6.3; Na, 7.6%.)

(d) The acid chloride was prepared as described above in (a) and 1 g. was shaken with excess concentrated aqueous ammonia, then the solid was filtered off and recrystallised from light petroleum to give the amide, in. 127 C. (Found: C, 81.5; H, 7.68; N, 4.95. C H ON requires: C, 81.6; H, 7.53; N, 4.85%).

The acid chloride was prepared as described above in (a) and 1 g. was dissolved in dryether and poured into a large excess of diazomethane. After 3 hours the mixture was evaporated to leave a yellow crystalline solid, which was taken up in dry methanol, silver oxide (1 g.) was added and the mixture was refluxed for 3 hours, filtered and evaporated. The residue in water was washed with ether, acidified and extracted with ether and the solution evaporated to give 3,5-dimethyl-6,6-diphenylhex- 5-en0ic acid, 111. C.

EXAMPLE 9 (a) Benzophenone (0.3 mole) in dry tetrahydrofuran (50 ml.) was added to a solution of vinyl magnesium bromide (0.3 mole) in dry tetrahydrofuran at 0 C. The mixture was allowed to stand for a few hours, then excess aqueous ammonium chloride was'added and the organic layer was separated, washed, dried and evaporated to give a clear oil. This oil was treated with 48% hydrobromic acid (0.5 mole) at 25 C. for 5 hours, then the resulting bromide was condensed with sodio-methyl diethyl malonate, and the ester was hydrolysed and decarboxylated as described in Example 7 to give on distillation Z-methyl-5,5-diphenylpent-4-enoic acid. (Found: C, 81.7; H, 6.9. C H O requires: C, 81.4; H, 6.8%.)

(b) This acid (2 g.) was treated with excess of bromine in dichloromethane for 30 minutes at room temperature.

The solution was washed with aqueous sodium thiosulphate and evaporated, and the resulting solid was recrystallised from t-butanol and light petroleum to give a dibromide, m. 135 C. (3 g.; 94%). This material was refluxed with potassium t-butoxide in t-butanol for 15 minutes, cooled, diluted with water and partitioned between 5% aqueous sodium hydroxide and ether. The ether layer was washed, dried and evaporated to give a white solid, presumed to be the lactone and having v 1760 cm.- (Nujol). The aqueous layer was acidified and extracted with ether, and treatment of the extract gave a mixture of starting acid and 2-methyl-5,5-diphenyl-4- brompent-4-enoic acid. The acids were esterified with diazomethane and the methyl esters were separated by gas-liquid chromatography.

EXAMPLE 10 By using the method of Example 6 1,1-diphenyl-2- hydroxymethylpent-l-ene (obtained from benzophenone and ethyl a-bromovalerate) was brominated and condensed with sodio-methyl diethyl malonate, and the resulting ester was hydrolysed and decarboxylated to give 2-methyl-4-diphenylmethyleneheptanoic acid as a gum.

EXAMPLE ll 2 Methyl-3,3-di- (4-methoxyphenyl)-prop-2-enoic acid (obtained from 4,4-dimethoxybenzophenone and ethyl a-bromopropionate) was reduced with lithium aluminum hydride, brominated with 48% hydrobromic acid and condensed with sodio-methyl diethyl malonate, hydrolysed and decarboxylated as described in Example 6 to give 2,4-dimethyl-5,5-di-(4-methoxyphenyl)-pent-4-en0ic acid as a gum.

EXAMPLE 12 2 Methyl-3-phenyl-3-(4-methoxyphenyl)-prop-2-enoic acid ethyl ester was prepared from p-methoxybenzophenone and ethyl a-bromopropionate. The intermediate ester was hydrolysed with ethanolic potassium hydroxide and worked up to give 2-methyl-3-phenyl-3-(4-meth0xyphenyl)pr0p-2-enoic acid, m.p. 12740 C. (Found: C, 76.0; H, 6.14. C H O requires: C, 76.1; H, 6.0.)

This acid was reduced, brominated and condensed with sodio-methyl diethyl malonate, then hydrolysed and decarboxylated as described in Example 6 to give 2,4-dimethyl (4 methoxy-phenyl)pent-4-en0ic acid, m. 1134 C.

6 We claim: 1. A substituted alkenoic acid of the formula of 1 to 6 carbon atoms; X is CH; or

cH -cH(C 3);

R is hydrogen, alkyl of 1 to 6 carbon atoms or hydrocarbon aryl of 6 to 10 carbon atoms; R is hydrogen or carboxyl, and each of R and R is hydrogen or alkoxy of 1 to 6 carbon atoms, except that when -R R are all hydrogen, R is not hydrogen and when R is hydrogen, at least one of R and R is alkoxy.

2. A compound according to Claim 1 wherein R is hydrogen, methyl or ethyl; X is CH R is hydrogen, methyl or ethyl; and each of R and R is hydrogen or methoxy, except that when R is hydrogen at least one of R and R is methoxy; or a non-toxic salt thereof.

3. LCarboxy-5,S-diphenyl-4-methylpent-4-enoic acids.

4. 2-Carboxy-2,4-dirnethyl 5,5 diphenylpent-4-enoic acid or a non-toxic salt thereof.

5. 2 Methyl 4 ethyl-5,5-dipheny1-2-carboxypent-4- enoic acid.

6. 2,4 Dimethyl 5,5 di-(4-methoxyphenyl)pent-4- enoic acid.

7. 2,4 Dimethyl-S-phenyl-S-(4-methoxy-pheny1)pent- 4-enoic acid.

References Cited Graham et al.: Chem. Abstracts, vol. 54 (1960), p. 7643bf.

JAMES A. PA'ITEN, Primary Examiner US. Cl. X.R.

260-469, 473 R, 475 SC, 515 P, 520 

